Alzheimer's disease (AD) begins with the memory impairment and synapse loss that is seen in Mild Cognitive Impairment (MCI). Genetic and biochemical evidence from studies of human AD patients and animal models suggest that AD is caused by elevated levels or ratios of the amyloid beta 1-42 protein, leading to the formation of oligomeric structures that are much more neuroactive than the monomeric or fibrillar structures (Catalano et al., '06). Abeta oligomers bind to neurons and potently block hippocampal long term plasticity (Lambert et al., '98, Wang et al., '02, '04, Walsh et al., '02, '05, Klyubin et al., '05, '08, Puzzo et al., '05, '08, Yun et al., '06, Shankar et al., '08), likely by altering glutamate receptor trafficking to the plasma membrane (Kamentz et al., '03, Hseih et al., '06). These changes lead to a transient synaptic spine regression (Shrestha et al.,'06, Calabrese et al., '06, Shankar et al., '07, Lacor et al., '07) and inhibition of learning and memory (Cleary et al., '05, Poling et al., '08). These transient deficits lead us to hypothesize that if Abeta oligomer effects can be prevented and/or reversed by inhibiting oligomer formation or binding to neurons, or by inhibiting their effects on signaling, it will prevent oligomer-induced memory deficits, and slow or reverse Alzheimer's disease progression in humans. This provides a strong rationale to test this hypothesis by discovering small molecule therapeutics that inhibit the effects of Abeta oligomers on the brain. These therapeutics would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Abeta oligomer-related diseases, including AD, MCI and Down's syndrome. We have established initial discovery activities for identifying a potent and bioavailable Abeta oligomer inhibitor IND candidate. We intend to capitalize on these efforts by screening our unique small molecule library with an assay measuring oligomer formation, determine active compound mechanism of action in primary neuron assays, determine compound structure, screen structural analogues and obtain pharmacokinetic data on active compounds. These activities will leave Cognition well positioned for future studies of compound efficacy in behavioral models of Alzheimer's disease. The project will result in a first-in-class oligomer formation inhibitor suitable for commercialization as a preclinical candidate. PUBLIC HEALTH RELEVANCE: Cognition Therapeutics is focused on the discovery of drugs that stop or reverse the cognitive decline associated with Alzheimer's disease and other neurodegenerative diseases. During this project we propose to discover Abeta oligomer inhibitors by screening our unique small molecule library with an assay measuring oligomer formation, determine active compound mechanism of action in primary neuron assays, determine compound structure, screen structural analogues and obtain pharmacokinetic data on active compounds. The project will result in a first-in-class oligomer formation inhibitor suitable for commercialization as a preclinical candidate.